Project Summary: Dry age-related macular degeneration (AMD) is the leading cause of vision loss in the Western World with a complex etiology. The fundamental abnormalities occurring in retinal pigment epithelial (RPE) cells, resulting in their progressive dysfunction and subsequent atrophy in AMD, are still not known. However, candidate pathogenic pathways linked to development of disease have emerged from the convergence of a sundry of epidemiological, genetic, morphological, and biochemical studies. Of these mechanistic pathways, three are strongly associated with initiation and progression of AMD and include inflammation, lipid dysregulation, and impaired protein degradation and clearance. Currently there are no drugs available to treat dry AMD. The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor activated by a diverse array of endogenous and environmental compounds including toxins and lipids. It has been studied extensively in the context of its role as a regulator of the cellular response to environmental toxicants. However, recent reports highlight non-classical mechanisms of AhR, most notably regulation of inflammatory pathways, cholesterol homeostasis, and autophagy/lysosomal function and permeability, pathways also important in the pathogenesis of AMD. Importantly, mechanisms regulated by AhR have been shown to be ligand and cell/tissue specific (e.g. toxic or pro-inflammatory response in one cell type yet anti-inflammatory in another cell type). As such, we are interested in investigating mechanisms underlying the AhR-mediated signal transduction pathway in RPE cells and the consequence of AhR activation on RPE health to counter injury and dysfunction. Our preliminary studies show that the activity of the AhR decreases as a function of age in human RPE cells. Additionally we have observed that aged AhR knockout (AhR-/-) mice develop phenotypic features of dry AMD, including thick continuous sub- RPE deposits, RPE dysfunction and degeneration, and accumulation of sub-retinal immune cells. Our findings not only support the potential importance of this signaling pathway in the pathogenesis of AMD, but also suggest an age-related compromise in AhR-mechanisms associated with normal RPE cellular clearance. Three specific aims have been proposed to test our hypothesis that the AhR represents a therapeutic target for prevention and treatment of AMD by simultaneously regulating aberrant cholesterol homeostasis and pro-inflammatory pathways in cells vulnerable in AMD.